Composition and method for treatment of diabetes

ABSTRACT

The present invention relates to a method of treating an incretin related disease such as diabetes, obesity and the like by delivery of butyric acid, bile acid, long chain fatty acid, or glutamine to the colon by bypassing the upper digestive tract.

This application claims priority of U.S. provisional application61/143,951 filed on Jan. 12, 2009 and U.S. provisional application61/293,773 filed on Jan. 11, 2010 and are included herein in theirentirety by reference.

COPYRIGHT NOTICE

A portion of the disclosure of this patent contains material that issubject to copyright protection. The copyright owner has no objection tothe reproduction by anyone of the patent document or the patentdisclosure as it appears in the Patent and Trademark Office patent filesor records, but otherwise reserves all copyright rights whatsoever.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a novel method and composition fortreating diabetes, metabolic syndrome, hypertriglyceridemia, andobesity. In particular, the present invention relates to the treatmentof diabetes, metabolic syndrome, hypertriglyceridemia and obesity bydelivering specific naturally occurring compounds to the lower gut orrectally.

2. Description of Related Art

Diabetes mellitus is a worldwide health threat of increasing magnitude,and is considered a major health risk both in developed and indeveloping countries. Type II diabetes accounts for the vast majority ofthe cases involving diabetes and accounts suggest it is the seventhleading cause of death in the United States. It appears that the majorcontributing factor to the incidence of Type II diabetes is beingoverweight. In the United States alone, it is estimated that over 17.6million individuals suffer from diabetes, and it is estimated that anadditional 5.7 million individuals are unaware they have diabetes. Inaddition, there are about 57 million Americans who are consideredpre-diabetic.

Type II diabetes is also known as non-insulin dependent diabetes. Itgenerally manifests itself as an inability to adequately regulateblood-glucose levels. This is as opposed to Type I diabetes which ischaracterized by defects in pancreatic production of insulin. In otherwords, it appears that Type II sufferers suffer from too little insulinor insulin resistance. The factors that have been identified incontributing to these Type II factors include one or more of obesity,genetic background, age, diet, and blood chemistry. Type II isfrequently called adult onset but because diet is a factor, it can ariseat virtually any age.

The results of diabetes Type II cause glucose levels to rise in theblood and urine which in turn can cause hunger, urination, thirst andmetabolism related issues. If the condition is not treated, the mostcommon serious results include heart, disease, kidney disease, andblindness. Several treatments are currently being used. Because obesityis frequently a causal agent in diabetes, diet and exercise are usuallya front line defense. Therapeutic agents are also used as a second lineof defense, including use of insulin or pharmaceuticals that reduceblood and urine levels of glucose.

Several drugs are in current use for diabetes Type II, including insulinsecretagogues, glucose lowering effectors, GLP-1 analogs, DPPIV,activators of the peroxisome proliferator activated receptor-gamma andalpha-glucosidase inhibitors. Because these current treatments haveseveral problems associated with them, there is still a need foralternative therapies to treat type II diabetes.

Gut hormones are a type of gastrointestinal hormone that, among others,cause an increase in the amount of insulin released from the beta cellsof the islets of Langerhans after eating, even before blood glucoselevels become elevated. They are secreted in their highest level fromL-cells in the colon. They also slow the rate of absorption of nutrientsinto the blood stream by reducing gastric emptying and may directlyreduce food intake. They also inhibit glucagon release from the alphacells of the Islets of Langerhans. Glucagon like peptide-1 (GLP-1),which is frequently called an incretin, is a gut hormone secreted by Lcells. Glucagon like peptide-1 (GLP-1) (an incretin) has been identifiedas one composition that if its secretion is stimulated can possibly beused to treat diabetes.

GLP-1 is a peptide secreted from enteroendocine L cells, and has a widevariety of physiological effects that have been described in numerouspublications over the past two decades. More recently, much research hasbeen focused on the use of GLP-1 in the treatment of conditions anddisorders, such as diabetes mellitus, stress, obesity, appetite controland satiety, Alzheimer's, inflammation, and diseases of the centralnervous system. However, the use of a peptide in clinical treatment isseverely limited due to difficult administration, and in vivo stability.Therefore, a small molecule that either mimicked the effects of GLP-1directly, or increased GLP-1 secretion, has been thought to be thetreatment of choice in increasing incretin production in treatment ofthe variety of conditions or disorders described above, namely diabetesmellitus and obesity.

PYY is a gut hormone (Peptide YY) which is a short (36 amino acid)protein released by cells in the ileum and colon in response to feeding.In humans, it appears to reduce appetite. PYY is found in L-cells in themucosa of the gastrointestinal trace especially in the ileum and colon.There is also a small amount of PYY about 1-10 percent in the esophagus,the stomach, the duodenum, and jejunum. PYY concentration in thecirculation increases postprandially (after food ingestion) anddecreases by fasting.

GLP-2 (a gut hormone) is a 33 amino acid peptide, co-secreted along withGLP-1 from intestinal endocrine cells in the small and large intestine.GLP-2, among others, stimulates mucosal growth in the small and largeintestine, inhibits gastric emptying, and gastric acid secretion,reduces intestinal permeability, and stimulates intestinal blood flow.

Oxyntomodulin (a gut hormone) is a 37 amino acid peptide co-secretedalong with GLP-1 from L-cells that mimics the effects of GLP-1 and GLP-2on gastric acid secretion and gut motility, suppresses appetite andreduces food intake in normal humans and reduces energy intake by ˜17%,in overweight and obese human subjects with no effect on water intake.

Butyric acid is a naturally occurring fatty acid occurring in the formof esters in animal fats and plant oils. For example, the triglycerideof butyric acid makes up 3% to 4% of butter. It is found in rancidfoods, such as butter and cheese, and has a very unpleasant smell andtaste. It is an important member of the fatty acid sub-group called theshort chain fatty acids.

Bile acids (also known as bile salts) are steroid acids foundpredominantly in the bile of mammals. In humans, taurocholic acid andglycocholic acid (derivatives of cholic acid) represent approximatelyeighty percent of all bile acids. The two major bile acids are cholicacid and chenodeoxycholic acid. They, their conjugates, and their7-alpha-dehydroxylated derivatives are all found in human intestinalbile. An increase in bile flow is exhibited with an increased secretionof bile acids. Bile acid's main function is to facilitate the formationof micelles, which promotes dietary fat processing. Bile saltsconstitute a large family of molecules, composed of a steroid structurewith four rings, a five, or eight carbon side-chain terminating in acarboxylic acid, and the presence and orientation of different numbersof hydroxyl groups. The four rings are labeled from left to right (ascommonly drawn) A, B, C, and D, with the D-ring being smaller by onecarbon than the other three. The hydroxyl groups have a choice of beingin 2 positions, either up (or out) termed beta (often drawn byconvention as a solid line), or down, termed alpha (seen as a dashedline in drawings). All bile acids have a hydroxyl group on position 3,which was derived from the parent molecule, cholesterol. In cholesterol,the 4 steroid rings are flat and the position of the 3-hydroxyl is beta.

Long chain fatty acids (LCFA) are fatty acids with aliphatic tails of 16carbons or more. Fatty acids are aliphatic monocarboxylic acids, derivedfrom, or contained in esterified form in an animal or vegetable fat,oil, or wax. Natural fatty acids commonly have a chain of 4 to 28carbons (usually unbranched and even numbered), which may be saturatedor unsaturated.

Glutamine is an amino acid that is used as a nutritional supplement inthe treatment of a variety of diseases, including cancer. Glutamine isthe most abundant free amino acid in the human body and, in addition toits role as a component of protein, serves a variety of functions in thebody. It is a non-essential amino acid because it is made by body cells.In addition, most dietary protein contains ample amounts of glutamine,and healthy people usually obtain all the additional glutamine that theyneed in their diet.

A number of new approaches to stimulation of the receptors which appearto stimulate gut hormones, such as the GPR 120, TGR5, GPR 41, and GPR 43receptors are being tried. In patent applications: WO/2008/067219published Jun. 5, 2008; US2007/060759 published Nov. 8, 2007; JP2006-6304A published Mar. 9, 2006; and JP 2006-56881 A published Mar. 2, 2006;there are disclosed several classes of small molecules agonists thathave been designed to stimulate the TGR5 receptor, a bile acidG-protein-coupled receptor.

The above naturally occurring products are difficult to administerorally with the colon being the target for pharmacological action,especially because taste of these products is extremely unpalatable, andthey are easily degraded in the digestive tract and/or absorbed.

Obesity is a medical condition that is reaching epidemic proportionsamong humans in a number of countries throughout the world. It is acondition that is also associated with, or induces other diseases orconditions that disrupt life's activities and lifestyles. Obesity isrecognized as a serious risk factor for other diseases and conditions,such as diabetes, hypertension, and arteriosclerosis, and can contributeto elevated levels of cholesterol in the blood. It is also recognizedthat increased body weight due to obesity can place a burden on joints,such as knee joints, causing arthritis, pain, and stiffness. Obesity cancontribute to certain skin conditions, such as atopic dermatitis and bedsores. Because overeating and obesity have become such a problem in thegeneral population, many individuals are now interested in losingweight, reducing weight, and/or maintaining a healthy body weight andlifestyle.

Hypertriglyceridemia (hTG) is a common disorder in the United States.The condition is exacerbated by uncontrolled diabetes mellitus, obesity,and sedentary habits, all of which are more prevalent in industrializedsocieties, particularly the United States, than in developing nations.In both epidemiologic and interventional studies, hypertriglyceridemiais a risk factor for coronary artery disease (CAD). Treatment ofhypertriglyceridemia is by restriction of carbohydrates and fats in thediet, as well as with niacin, fibrates and statins (three classes ofdrugs). Increased fish oil intake may substantially lower anindividual's triglycerides.

There are obviously a number of compositions designed to deliver amedicament to the lower gut. One in particular are the three-componentmatrix structures, such as disclosed in U.S. Pat. No. 7,431,943 to Villaet al. issued Oct. 7, 2008 and incorporated herein in its entirety byreference.

A number of different formulations are available for delivery of desiredcompositions to the colon including amylose coated tablets, entericallycoated chitosan tablets, matrix within matrix or multimatrix systems, orpoly-saccaride coated tablets. One example of multimatrix controlledrelease systems are disclosed in U.S. Pat. No. 7,431,943 issued Oct. 7,2008 to Villa et al. and incorporated herein by reference. Disclosed isa matrix within matrix design wherein a lipophilic phase and amphiphilicphase are incorporated within the inner matrix and at least a portion ofthe active ingredient is incorporated into the amphiphilic phase.

BRIEF SUMMARY OF THE INVENTION

The present invention relates to the discovery that certain naturallyoccurring compositions can be delivered to the colon or rectallybypassing the stomach and upper digestive system and increase theproduction of certain gut hormones from L cells.

Therefore, in one embodiment, the present invention therefore is amethod of treating or preventing a condition or disorder affected by thedecrease or lack of release of a gut hormone secreted from L cells bystimulating the production of an L cell secreted gut hormone in thecolon of an individual comprising:

-   -   a) selecting an agent causing gut hormone secretion from L-cells        from the group comprising butyric acid, a bile acid, a long        chain fatty acid and glutamine, the composition formulated to        release in a colon targeted delivery system or in a rectal        release system; and    -   b) administering sufficient stimulating pharmaceutical        composition to the individual sufficient to cause a release of        gut hormones from the L-cell in the colon of the individual        sufficient to achieve the desired result.

DETAILED DESCRIPTION OF THE INVENTION

While this invention is susceptible to embodiment in many differentforms, there is shown in the drawings and will herein, be described indetail specific embodiments, with the understanding that the presentdisclosure of such embodiments is to be considered as an example of theprinciples and not intended to limit the invention to the specificembodiments shown and described. In the description below, likereference numerals are used to describe the same, similar, orcorresponding parts in the several views of the drawings. This detaileddescription defines the meaning of the terms used herein andspecifically describes embodiments in order for those skilled in the artto practice the invention.

The terms “a” or “an”, as used herein, are defined as one or as morethan one. The term “plurality”, as used herein, is defined as two or asmore than two. The term “another”, as used herein, is defined as atleast a second or more. The terms “including” and/or “having”, as usedherein, are defined as comprising (i.e., open language). The term“coupled”, as used herein, is defined as connected, although notnecessarily directly, and not necessarily mechanically.

Reference throughout this document to “one embodiment”, “certainembodiments”, and “an embodiment” or similar terms means that aparticular feature, structure, or characteristic described in connectionwith the embodiment is included in at least one embodiment of thepresent invention. Thus, the appearances of such phrases or in variousplaces throughout this specification are not necessarily all referringto the same embodiment. Furthermore, the particular features,structures, or characteristics may be combined in any suitable manner inone or more embodiments without limitation.

The term “or”, as used herein, is to be interpreted as an inclusive ormeaning any one or any combination. Therefore, “A, B or C” means any ofthe following: “A; B; C; A and B; A and C; B and C; A, B and C”. Anexception to this definition will occur only when a combination ofelements, functions, steps or acts are in some way inherently mutuallyexclusive.

The drawings featured in the figures, if any are for the purpose ofillustrating certain convenient embodiments of the present invention,and are not to be considered as limitation thereto. Term “means”preceding a present participle of an operation indicates a desiredfunction for which there is one or more embodiments, i.e., one or moremethods, devices, or apparatuses for achieving the desired function andthat one skilled in the art could select from these or their equivalentin view of the disclosure herein and use of the term “means” is notintended to be limiting.

As used herein, the term “treating” refers to alleviating the specifiedcondition, eliminating or reducing the symptoms of the condition,slowing or eliminating the progression of the condition and preventingor delaying the initial occurrence of the condition in a subject, orreoccurrence of the condition in a previously afflicted subject.

As used herein, a “condition or disorder” refers to any disease state, aparticular state of a mammal or the like to which an increase in theproduction of a gut hormone from L cells would affect in a positive ornegative way. Included are the disease states noted herein, but ingeneral, this refers to any state so affected by increasing a guthormone from L cells in a desired manner. The gut hormone system isknown in mammals and as such the present invention relates to thetreatment of a mammal. In one embodiment, the mammal is a human.Conditions for treatment by increasing a gut hormone from L cellsproduction include, but are not limited to, Type I diabetes, Type IIdiabetes, obesity, appetite control, metabolic syndrome, and polycysticovary syndrome.

The gut hormone secretion in the present invention is stimulated inL-cells present in the colon, normally in response to the presence ofnutrients in the gut. While such cells are present in other parts of thedigestive tract and other parts of the organism, they have the highestconcentration in the colon. Stimulation of L-cells in the colon resultsin the most effective production of gut hormones possible and thus, themost effective treatment. Gut hormones from L-cells of the presentinvention include, but are not limited to, GLP-1, GP-2, PYY andoxyntomodulin. Incretins such as GLP-1, in particular, are a gut hormoneof interest in one embodiment.

The compounds of the invention for stimulating gut hormone release arenatural compounds selected from the group comprising butyric acid, abile acid, a long chain fatty acid, and glutamine. It is understood thatthis includes combinations of the compounds as well as each compoundindividually.

As used herein, “a compound” of the present invention includes allcompounds described herein.

The compounds of the present invention may crystallize in more than oneform, a characteristic known as polymorphism, and such polymorphic forms(“polymorphs”) are within the scope of the present invention.Polymorphism generally can occur as a response to changes intemperature, pressure, or both. Polymorphism can also result fromvariations in the crystallization process. Polymorphs can bedistinguished by various physical characteristics known in the art, suchas x-ray diffraction patterns, solubility, and melting point.

Certain of the compounds described herein, contain one or more chiralcenters, or may otherwise be capable of existing as multiplestereoisomers. The scope of the present invention includes mixtures ofstereoisomers as well as purified enantiomers orenantiomerically/diastereomerically enriched mixtures. Also, includedwithin the scope of the invention are the individual isomers of thecompounds of the present invention, as well as any wholly or partiallyequilibrated mixtures thereof. The present invention also includes theindividual isomers of the compounds represented by the formulas above asmixtures with isomers, thereof, in which one or more chiral centers areinverted.

Typically, but not absolutely, the compounds herein, include the saltsof the present compositions and include the pharmaceutically acceptablesalts. Salts encompassed within the term “pharmaceutically acceptablesalts” refer to non-toxic salts of the compounds of this invention.Salts of the compounds of the present invention may include acidaddition salts. Representative salts include acetate, benzenesulfonate,benzoate, bicarbonate, bisulfate, bitartrate, borate, calcium edetate,camsylate, carbonate, clavulanate, citrate, dihydrochloride, edisylate,estolate, esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylsulfate, monopotassium maleate, mucate, napsylate, nitrate,N-methylglucamine, oxalate, pamoate (embonate), palmitate, pantothenate,phosphate/diphosphate, polygalacturonate, potassium, salicylate, sodium,stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate,tosylate, thethiodide, thmethylammonium, and valerate salts. Othersalts, which are not pharmaceutically acceptable, may be useful in thepreparation of compounds of this invention, and these should beconsidered to form a further aspect of the invention.

The “administering” of a composition of the present invention can referto oral, rectal, IV, IM or the like, and is not dependant on anyparticular means of administration. As described elsewhere herein, thecompounds are so formulated to be taken so as to bypass the upperdigestive tract and stomach or rectally to deliver the composition tothe colon.

As used herein, the term “effective amount” means that amount of a drugor pharmaceutical agent that will elicit the biological or medicalresponse of a tissue, system, animal, or human that is being sought, forinstance, by a researcher or clinician.

The term “therapeutically effective amount” means any amount which, ascompared to a corresponding subject who has not received such amount,results in improved treatment, healing, prevention, or amelioration of adisease, disorder, or side effect, or a decrease in the rate ofadvancement of a disease or disorder. The term also includes within itsscope amounts effective to enhance normal physiological function. Atherapeutically effective amount will produce a “therapeutic effect”.

For use in therapy, therapeutically effective amounts of a compound ofthe present invention, as well as salts thereof, are presented as apharmaceutical composition formulated to release in a colon targeteddelivery system.

The present invention provides pharmaceutical compositions that includeeffective amounts of a compound as herein described, or a salt thereof,and one or more pharmaceutically acceptable carriers, diluents, orexcipients. The carrier(s), diluent(s) or excipient(s) must beacceptable, in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient of thepharmaceutical composition and consistent with the mode ofadministration, i.e., oral or rectal.

In accordance with another aspect of the invention, there is alsoprovided a process for the preparation of a pharmaceutical formulation,including admixing a compound of the present invention or salts thereof,with one or more pharmaceutically acceptable carriers, diluents orexcipients.

A therapeutically effective amount of a compound of the presentinvention will depend upon a number of factors. For example, thespecies, age, and weight of the recipient, the precise conditionrequiring treatment and its severity, the nature of the formulation, andthe type of colon targeted delivery system are all factors to beconsidered. The therapeutically effective amount ultimately should be atthe discretion of the attendant, physician, or veterinarian. Regardless,an effective amount of a gut hormone compound of the present inventionfor the treatment of humans suffering from diabetes or an overweightcondition and associated conditions, generally, should be in the rangeof 0.01 to 100 mg/kg body weight of recipient (mammal) per day. Moreoften, the effective amount should be in the range of 0.3 to 30 mg/kgbody weight per day. Thus, for a 70 kg adult mammal the actual amountper day would usually be from 21 to 2100 mg. This amount may be given ina single dose per day or in a number (such as two, three, four, five, ormore) of sub-doses per day such that the total daily dose is the same.An effective amount of a salt or solvate thereof, may be determined as aproportion of the effective amount of the compound of the presentinvention per se. Similar dosages should be appropriate for treatment ofthe other conditions referred to herein.

Pharmaceutical formulations may be presented in unit dose formscontaining a predetermined amount of active ingredient per unit dose.Such a unit may contain, as a non-limiting example, 0.5 mg to 1 g of acompound of the present invention, depending on the condition beingtreated, the route of administration, and the age, weight, and conditionof the patient. Preferred unit dosage formulations are those containinga daily dose or sub-dose, as herein above recited, or an appropriatefraction thereof, of an active ingredient. Such pharmaceuticalformulations may be prepared by any of the methods well known in thepharmacy art.

The compounds of the present invention, or a salt thereof, areadministered by a targeted drug delivery system. In one embodiment, thedelivery systems may be employed for targeting drug delivery to thecolon and bypassing the upper digestive system and stomach. Such drugdelivery systems include covalent linkage compositions, polymer coatedcompositions, compositions embedded in matrices, time releasedcompositions, redox-sensitive polymer compositions, bioadhesivecompositions, micropartical coating compositions, and osmotic deliverycompositions. Suitable compositions include those containingpolysaccharides, such as chitosan, pectin, chondroitin sulphate,cyclodexthn, dextrans, guar gum, inulin, amylose and locust bean gum.The compounds may also be coupled with soluble polymers. Such polymerscan include polyvinylpyrrolidone (PVP), pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethyl-aspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds may becoupled to a class of biodegradable polymers; for example, polylacticacid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, andcross-linked or amphipathic block copolymers of hydrogels. Those ofparticular effectiveness in the present invention include embodiments ofmultimatrix targeted systems. Of particular effectiveness in the presentinvention are the targeted matrix in matrix systems comprising aformulation of a hydrophilic first matrix, comprising a lipophilic phaseand an amphiphilic phase, wherein the lipophilic phase and theamphiphilic phase are in a second matrix together and the second matrixis dispersed throughout the hydrophilic first matrix and wherein thepharmaceutical composition containing the compound is at least partiallyincorporated into the amphiphilic phase. Examples of some of the matrixin matrix formulations are disclosed in U.S. Pat. No. 7,431,943 notedabove. Those skilled in the art will appreciate the use of suchcompositions for the purposes of targeting delivery of the compounds ofthe present invention, or a salt thereof, to the colon of the subjectbeing treated. The methods for the formulation of such compositions fortargeted delivery are within the skill in the art, in view of thisdisclosure.

The compounds of the present invention or a salt thereof may be employedalone or in combination with other therapeutic agents. The compound(s)of the present invention and the other pharmaceutically active agent(s)may be administered together or separately and, when administeredseparately, administration may occur simultaneously or sequentially, inany order. The amounts of the compound(s) of the present invention andthe other pharmaceutically active agent(s) and the relative timings ofadministration will be selected in order to achieve the desired combinedtherapeutic effect. The administration in combination of a compound ofthe present invention or a salt or solvate thereof with other treatmentagents may be in combination by administration concomitantly in: (1) aunitary pharmaceutical composition, including both compounds; or (2)separate pharmaceutical compositions, each including one of thecompounds. Alternatively, the combination may be administered separatelyin a sequential manner wherein one treatment agent is administered firstand the other second or vice versa. Such sequential administration maybe close in time or remote in time.

The compounds may also be formulated in rectal compositions such assuppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter or other glycerides. Thecompositions so formulated will be designed to give an effective dosageto the colon in addition to other areas a rectal administration mightaffect.

The compounds of the present invention may be used in the treatment of avariety of disorders and conditions. As such, the compounds of thepresent invention may be used in combination with a variety of othertherapeutic agents useful in the treatment of those disorders orconditions. As discussed briefly above, current diabetes therapiesinclude diet, exercise, insulin, insulin secretagogues, glucose-loweringeffectors, PPAR-γ agonists, and α-glucosidase inhibitors. The compoundsof the present invention may be combined with these or other medicaltherapies to treat and/or prevent diabetes and associated disorders andconditions, including but not limited to, diabetes Types I and II,obesity, glucose intolerance, insulin resistance, metabolic syndrome,hyperlipidemia, hypercholesterolemia, arteriosclerosis,neurodegenerative diseases, and other indications such as inflammationand stroke. For example, in the treatment of Type II diabetes, acompound of the present invention may be combined with one or morepharmaceutically active agents, including metformin, sulfonylureas suchas glyburide and glipizide, repaglinide, nateglinide, thiazolidinedionessuch as rosiglitazone and pioglitazone, acarbose, miglitol, exanatide,pramlintide, and insulin.

EXAMPLES Example 1

10 overnight fasted obese diabetic patients with impaired gut hormoneeffect³ and/or impaired gut hormone secretion^(4.5) are dosed rectallywith 1 g of glutamine delivered as an enema. Blood is collected atfollowing time points: −30, −5, 5; 10, 15, 30, and 60 minutes. Blood isanalyzed for levels of: glucose, insulin, GLP-1, PYY, and otherhormones.

Example 2

10 overnight fasted obese diabetic patients with impaired gut hormoneeffect³ and/or impaired gut hormone secretion^(4.5) are dosed rectallywith suppositories (made as described in¹) or enema (containing 1 g ofglutamine). 30 minutes after drug administration, patients are subjectedto Oral Glucose Tolerance Test (OGTT). Blood is collected at followingtime points: −30, 0, 5, 10, 15, 30, 60, 90, and 120 minutes. Blood isanalyzed for levels of: glucose, insulin, GLP-1, PYY, and otherhormones. Glucose levels are measured to decrease after treatmentregime.

Example 3

10 overnight fasted obese diabetic patients with impaired gut hormoneeffect³ and/or impaired gut hormone secretion^(4.5) are dosed rectallywith suppositories (made as described in¹) or enema (containing 2 g ofbutyric acid). 30 minutes after drug administration, patients aresubjected to Oral Glucose Tolerance Test (OGTT). Blood is collected atfollowing time points: −30, 0, 5, 10, 15, 30, 60, 90, and 120 minutes.Blood is analyzed for levels of: glucose, insulin, GLP-1, PYY, and otherhormones. Glucose levels are measured to decrease after treatmentregime.

Example 4

Tables formulated with MMX technology (containing 1 g of glutamine) aremade as described in². 10 overnight fasted obese diabetic patients withimpaired incretin effect³ are dosed with one MMX tablet in the morning.4 hours after drug administration, patients are subjected to OralGlucose Tolerance Test (OGTT). Blood is collected at following timepoints: −30, 0, 5, 10, 15, 30, 60, 90, and 120 min. Blood is analyzedfor levels of: glucose, insulin, GLP-1, PYY, and other hormones. Glucoselevels are measured to decrease after treatment regime.

Example 5

Tables formulated with MMX technology (containing 2 g of butyric acid)are made as described in². 10 overnight fasted obese diabetic patientswith impaired incretin effect³ are dosed with one MMX tablet in themorning. 4 hours after drug administration, patients are subjected toOral Glucose Tolerance Test (OGTT). Blood is collected at following timepoints: −30, 0, 5, 10, 15, 30, 60, 90, and 120 min. Blood is analyzedfor levels of: glucose, insulin, GLP-1, PYY, and other hormones. Glucoselevels are measured to decrease after treatment regime.

Example 6

Tablets formulated with MMX technology (containing 1 g of glutamine) aremade as described in². 10 obese diabetic patients with impaired incretineffect³ are dosed with one MMX tablet in the morning before first mealfor six (6) weeks. HbA1c, fasting glucose, and insulin are measuredbefore treatment and at 1, 2, and 6 weeks after initiation of thetreatment. Additionally, patients are subjected at these times to OralGlucose Tolerance Test (OGTT). Blood is collected at following timepoints: −30, 0, 5, 10, 15, 30, 60, 90, and 120 min. Blood is analyzedfor levels of: glucose, insulin, GLP-1, PYY, and other hormones. Glucoselevels are measured to decrease after treatment regime.

Example 7

Tables formulated with MMX technology (containing 2 g of butyric acid)are made as described in². 10 obese diabetic patients with impairedincretin effect³ are dosed with one MMX tablet in the morning beforefirst meal for six (6) weeks. HbA1c, fasting glucose and insulin aremeasured before the treatment and at 1, 2, and 6 weeks after initiationof the treatment. Additionally, patients are subjected at these times toOral Glucose Tolerance Test (OGTT). Blood is collected at following timepoints: −30, 0, 5, 10, 15, 30, 60, 90, and 120 min. Blood is analyzedfor levels of: glucose, insulin, GLP-1, PYY, and other hormones. Glucoselevels are measured to decrease after treatment regime.

1. Mayo Clin. Proc. 1993, Vol 68, 978 incorporated herein by reference.

-   2. U.S. Pat. No. 7,431,943 B1 incorporated herein by reference.-   3. Diabetes, Obesity and Metabolism, 9 (Suppl. 1), 2007, 23-31    incorporated herein by reference.-   4. Toft-Nielsen M B, Damholt M B, Madsbad S et al. Determinants of    the impaired secretion of glucagon-like peptide-1 in type 2 diabetic    patients. J Clin Endocrinol Metab 2001; 86:3717-3723.-   5. Rask E, Olsson T, Soderberg S et al. Impaired incretin response    after a mixed meal is associated with insulin resistance in    nondiabetic men. Diabetes Care 2001; 24:1640-1645.

What is claimed is:
 1. A method of treating type I diabetes, type IIdiabetes, hypertriglyceridemia, obesity, appetite control, metabolicsyndrome, or polycystic ovary syndrome affected by the decrease or lackof release of a gut hormone secreted from L-cells comprising stimulatingthe production of an L-cell secreted gut hormone in the colon of anindividual method comprising the steps of: a) selecting a compositioncausing gut hormone secretion from L-cells from the group comprisingbutyric acid, and glutamine, the composition formulated to release in acolon targeted delivery system or in a rectal release system; and b)administering sufficient stimulating pharmaceutical composition to theindividual colon or rectum sufficient to cause a release of gut hormonesfrom the L-cell in the colon of the individual sufficient to achieve thedesired result.
 2. A method according to claim 1 wherein the compositioncomprises glutamine.
 3. A method according to claim 1 wherein thecomposition comprises butyric acid.
 4. A method according to claim 1wherein the colon targeted delivery system is a matrix within matrixdelivery system.
 5. A method according to claim 4 wherein the colontargeted delivery system is a controlled release formulation of ahydrophilic first matrix comprising a lipophilic phase and anamphiphilic phase wherein the lipophilic phase and the amphiphilic phaseare in a second matrix together and said second matrix is dispersedthroughout the hydrophilic first matrix wherein the agent is at leastpartially incorporated into the amphiphilic phase.
 6. A composition forinducing the release of a gut hormone from L-cells in the colon whereinthe composition comprises a composition selected from the groupcomprising butyric acid, and glutamine formulated such that it does notrelease in either the stomach or upper gastro intestinal tract.
 7. Acomposition according to claim 6 wherein the composition is formulatedin a colon targeted drug delivery system.
 8. A composition according toclaim 6 wherein the composition is formulated for rectal administration.9. A composition according to claim 6 wherein the composition comprisesglutamine.
 10. A composition according to claim 6 wherein thecomposition comprises butyric acid.
 11. A composition according to claim7 wherein the colon targeted delivery system is a matrix within matrixsystem.
 12. A composition according to claim 11 wherein the colontargeted delivery system is a controlled-release formulation of ahydrophilic first matrix comprising a lipophilic phase and anamphiphilic phase wherein the lipophilic phase and the amphiphilic phaseare in a second matrix together and said second matrix is dispersedthroughout the hydrophilic first matrix wherein the composition is atleast partially incorporated into the amphiphilic phase.